Combined Dynamic Kinetic Resolution and C−H Functionalization for Facile Synthesis of Non-Biaryl-Atropisomer-Type Axially Chiral Organosilanes

Although asymmetric C−H functionalization has been available for the synthesis of structurally diverse molecules, catalytic dynamic kinetic resolution (DKR) approaches to change racemic stereogenic axes remain synthetic challenges in this field. Here, a concise palladium-catalyzed DKR was combined with C−H functionalization involving olefination and alkynylation for the highly efficient synthesis of non-biaryl-atropisomer-type (NBA) axially chiral oragnosilanes. The chemistry proceeded through two different and distinct DKR: first, an atroposelective C−H olefination or alkynylation produced axially chiral vinylsilanes or alkynylsilanes as a new family of non-biaryl atropisomers (NBA), and second, the extension of this DKR strategy to twofold o,o′-C−H functionalization led to the multifunctional axially chiral organosilicon compounds with up to >99 % ee.     

Catalytic Atroposelective C7 Functionalisation of Indolines and Indoles

Axially chiral atropisomeric compounds are widely applied in asymmetric catalysis and medicinal chemistry. In particular, axially chiral indole- and indoline-based frameworks have been recognised as important heterobiaryl classes because they are the core units of bioactive natural alkaloids, chiral ligands and bioactive compounds. Among them, the synthesis of C7-substituted indole biaryls and the analogous indoline derivatives is particularly challenging, and methods for their efficient synthesis are in high demand. Transition-metal catalysis is considered one of the most efficient methods to construct atropisomers. Here, we report the enantioselective synthesis of C7-indolino- and C7-indolo biaryl atropisomers by means of C−H functionalisation catalysed by chiral RhJasCp complexes.     

Construction of C-N Atropisomers by Aminocatalytic Enantioselective Addition of Indole-2-carboxaldehydes to o-Quinone Derivatives

The first atroposelective aminocatalytic methodology for the construction of C−N atropisomers is presented. The synthesis of this class of axially chiral molecules typically encompasses substrates in which the C−N bond is pre-formed. In contrast, this work presents the direct coupling of indole-2-carboxaldehydes to ortho-quinones, to form the stereogenic C−N axis in an atroposelective way. Application of typical secondary amine catalysts furnished the desired product, however, in low yields and as a complex mixture arising from poor regiocontrol among the C₃- and N₁-sites of the indole core. A new aminocatalyst was designed and synthesized with increased outer-sphere steric bulk to address these challenges thereby providing good levels of regio- and enantioselectivity. A novel library of functionalized and enantioenriched C−N atropisomers was obtained and their synthetic utility was demonstrated by various transformations.     

Construction of Axially Chiral Arylpyrroles via Atroposelective Diyne Cyclization

Axially chiral biaryls widely exist in natural products and pharmaceuticals and are used as chiral ligands and catalysts in asymmetric synthesis. Compared to the well-established axially chiral 6-membered biaryl skeletons, examples of 5-membered biaryls have been quite scarce, and mono-substituted 3-arylpyrrole atropisomers have not been reported. Here, we disclose a copper-catalyzed atroposelective diyne cyclization for the construction of a range of axially chiral arylpyrrole biaryls in good to excellent yields with generally excellent enantioselectivities via oxidation and X−H insertion of vinyl cations. Importantly, this protocol not only represents the first synthesis of mono-substituted 3-arylpyrrole atropisomers, but also constitutes the first example of atroposelective diyne cyclization and the first atropisomer construction via vinyl cations. Theoretical calculations further support the mechanism of vinyl cation-involved cyclization and elucidate the origin of enantioselectivity.     

Enantioselective Synthesis of C−O Axially Chiral Diaryl Ethers by NHC-Catalyzed Atroposelective Desymmetrization**

Axially chiral diaryl ethers, a distinguished class of atropisomers possessing unique dual C−O axis, hold immense potential for diverse research domains. In contrast to the catalytic enantioselective synthesis of conventional single axis bearing atropisomers, the atroposelective synthesis of axially chiral ethers containing flexible C−O axis remains a significant challenge. Herein, we demonstrate the first N-heterocyclic carbene (NHC)-catalyzed synthesis of axially chiral diaryl ethers via atroposelective esterification of dialdehyde-containing diaryl ethers. Mechanistically, the reaction proceeds via NHC-catalyzed desymmetrization strategy to afford the corresponding axially chiral diaryl ether atropisomers in good yields and high enantioselectivities under mild conditions. The derivatization of the synthesized product expands the utility of present strategy via access to a library of C−O axially chiral compounds. The temperature dependency and preliminary investigations on the racemization barrier of C−O bonds are also presented.     

Rhodium-Catalyzed ortho-Olefination of Sterically Demanding Benzamides: Application to the Asymmetric Synthesis of Axially Chiral Benzamides

It has been established that an unsubstituted cyclopentadienyl rhodium(III) (CpRh^III) complex is a highly active catalyst for the aerobic oxidative ortho C−H bond olefination of sterically demanding ortho-substituted benzamides with alkenes. This catalysis was successfully applied to the diastereoselective synthesis of axially chiral N,N-dialkylbenzamides. The combination of the ruthenium(II)-catalyzed enantioselective hydrogenation and the CpRh^III-catalyzed diastereoselective ortho C−H bond olefination enabled the asymmetric synthesis of axially chiral N,N-dialkylbenzamide derivatives with high ee values.     

Organocatalytic Enantioselective Synthesis of Axially Chiral N,N′-Bisindoles

This study establishes the first organocatalytic enantioselective synthesis of axially chiral N,N′-bisindoles via chiral phosphoric acid-catalyzed formal (3+2) cycloadditions of indole-based enaminones as novel platform molecules with 2,3-diketoesters, where de novo indole-ring formation is involved. Using this new strategy, various axially chiral N,N′-bisindoles were synthesized in good yields and with excellent enantioselectivities (up to 87 % yield and 96 % ee). More importantly, this class of axially chiral N,N′-bisindoles exhibited some degree of cytotoxicity toward cancer cells and was derived into axially chiral phosphine ligands with high catalytic activity. This study provides a new strategy for enantioselective synthesis of axially chiral N,N′-bisindoles using asymmetric organocatalysis and is the first to realize the applications of such scaffolds in medicinal chemistry and asymmetric catalysis.     

N-Aryl indole-derived C–N bond axially chiral phosphine ligands: synthesis and application in palladium-catalyzed asymmetric allylic alkylation

N-Aryl indole-derived C–N bond axially chiral phosphine ligands 2a–c were obtained by DDQ oxidation of N-aryl indoline-derived phosphine oxide followed by silane reduction. Resolution of C–N bond atropisomers was achieved by chiral HPLC. The investigation of the rotation barrier for the C–N bond axial stability of phosphines and the determination of the absolute configuration of 2c are described. Finally, the ability of the chiral ligand 2c was demonstrated in a palladium-catalyzed asymmetric allylic alkylation (up to 99% ee).     

Asymmetric Synthesis of Axially Chiral C−N Atropisomers

Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral ligands for asymmetric catalysis and smart materials. Although most of these compounds are biaryls and heterobiaryls displaying a C−C stereogenic axis, there is a growing interest in less common and more challenging axially chiral C−N atropisomers. This review offers an overview of the various methodologies available for their asymmetric synthesis. A brief introduction is initially given to contextualize these axially chiral skeletons, including a historical background and examples of natural products containing axially chiral C−N axes. The preparation of different families of C−N based atropisomers is then presented from anilides to chiral five- and six-membered ring heterocycles. Special emphasis has been given to modern catalytic asymmetric strategies over the past decade for the synthesis of these chiral scaffolds. Applications of these methods to the preparation of natural products and biologically active molecules will be highlighted along the text.     

Atropisomeric carbohydrate imidazolidines: a novel class of nonbiaryl atropisomers

Stable axially chiral atropisomers have been prepared by reaction of 2-aminosugars with o,o′-disubstituted aryl isocyanates and isothiocyanates; these rotationally restricted heterobiaryls constitute a novel class of atropisomers for use in atroposelective reactions.     

Atroposelective PIII/PV=O Redox Catalysis for the Isoquinoline-Forming Staudinger–aza-Wittig Reaction

Herein, we describe the feasibility of atroposelective P^III/P^V=O redox organocatalysis by the Staudinger–aza-Wittig reaction. The formation of isoquinoline heterocycles thereby enables the synthesis of a broad range of valuable atropisomers under mild conditions with enantioselectivities of up to 98 : 2 e.r. Readily prepared azido cinnamate substrates convert in high yield with stereocontrol by a chiral phosphine catalyst, which is regenerated using a silane reductant under Brønsted acid co-catalysis. The reaction provides access to diversified aryl isoquinolines, as well as benzoisoquinoline and naphthyridine atropisomers. The products are expeditiously transformed into N-oxides, naphthol and triaryl phosphine variants of prevalent catalysts and ligands. With dinitrogen release and aromatization as ideal driving forces, it is anticipated that atroposelective redox organocatalysis provides access to a multitude of aromatic heterocycles with precise control over their configuration.     

Atroposelective Synthesis of Axially Chiral Styrenes by Platinum- Catalyzed Stereoselective Hydrosilylation of Internal Alkynes

Hydrofunctionalization of alkynes is one of the most efficient ways to access axially chiral styrenes with open-chained olefins. While great advances have been achieved for 1-alkynylnaphthalen-2-ols and analogues, atroposelective hydrofunctionalization of unactivated internal alkynes lags. Herein we reported a platinum-catalyzed atroposelective hydrosilylation of unactivated internal alkynes for the first time. With monodentate TADDOL-derived phosphonite L1 used as a chiral ligand, various axially chiral styrenes were achieved in excellent enantioselectivities with high E-selectivities. Control experiments showed that the NH-arylamide groups have significant effects on both the yields and enantioselectivities and could act as directing groups. The potential utilities of the products were shown by the transformations of the amide motifs of the products.     

Asymmetric Synthesis of Axially Chiral Isoquinolones: Nickel‐Catalyzed Denitrogenative Transannulation

The first Ni⁰/bis(oxazoline)‐catalyzed asymmetric denitrogenative transannulation of 1,2,3‐benzotriazin‐4(3H)‐ones with bulky internal alkynes to form novel axially chiral isoquinolones in an atroposelective manner has been developed. This method provides direct asymmetric access to axially chiral isoquinolones with excellent functional‐group tolerance in excellent yields and stereoselectivities from readily available starting materials under mild reaction conditions. These axially chiral isoquinolones exhibit high cytotoxicity against a number of human cancer cell lines. DFT calculations reveal the nature of the transition state in the key annulation step.     

Synthesis of Axially Chiral Styrenes through Pd-Catalyzed Asymmetric C−H Olefination Enabled by an Amino Amide Transient Directing Group

The atroposelective synthesis of axially chiral styrenes remains a formidable challenge due to their relatively lower rotational barriers compared to the biaryl atropoisomers. Herein, we describe the construction of axially chiral styrenes through Pd^II-catalyzed atroposelective C−H olefination, using a bulky amino amide as a transient chiral auxiliary. Various axially chiral styrenes were produced with good yields and high enantioselectivity (up to 95 % yield and 99 % ee). Carboxylic acid derivatives of the resulting axially chiral styrenes showed superior enantiocontrol over the biaryl counterparts in Co^III-catalyzed enantioselective C(sp³)−H amidation of thioamide. Mechanistic studies suggest that C−H cleavage is the enantioselectivity-determining step.     

A Dynamic Kinetic Resolution Approach to Axially Chiral Diaryl Ethers by Catalytic Atroposelective Transfer Hydrogenation

Diaryl ethers are widespread in biologically active compounds, ligands and catalysts. It is known that the diaryl ether skeleton may exhibit atropisomerism when both aryl rings are unsymmetrically substituted with bulky groups. Despite recent advances, only very few catalytic asymmetric methods have been developed to construct such axially chiral compounds. We describe herein a dynamic kinetic resolution approach to axially chiral diaryl ethers via a Brønsted acid catalyzed atroposelective transfer hydrogenation (ATH) reaction of dicarbaldehydes with anilines. The desired diaryl ethers could be obtained in moderate to good chemical yields (up to 79 %) and high enantioselectivities (up to 95 % ee) under standard reaction conditions. Such structural motifs are interesting precursors for further transformations and may have potential applications in the synthesis of chiral ligands or catalysts.     

Access to Aryl‐Naphthaquinone Atropisomers by Phosphine‐Catalyzed Atroposelective (4+2) Annulations of δ‐Acetoxy Allenoates with 2‐Hydroxyquinone Derivatives

Although asymmetric phosphine catalysis is a powerful tool for the construction of various chiral carbon centers, its synthetic potential toward an enantioenriched atropisomer has not been explored yet. Reported herein is a phosphine‐catalyzed atroposelective (4+2) annulation of δ‐acetoxy allenoates and 2‐hydroxyquinone derivatives. The reaction provides expedient access to aryl‐naphthaquinone atropisomers by the de novo construction of a benzene ring. The two functionalities of the catalyst, a tertiary phosphine (Lewis base) and a tertiary amine (Brønsted base), cooperatively enable this process with high regio‐ and enantioselectivities.     

Synthesis of Axially Chiral Styrenes through Pd‐Catalyzed Asymmetric C−H Olefination Enabled by an Amino Amide Transient Directing Group

The atroposelective synthesis of axially chiral styrenes remains a formidable challenge due to their relatively lower rotational barriers compared to the biaryl atropoisomers. Herein, we describe the construction of axially chiral styrenes through Pd^II‐catalyzed atroposelective C?H olefination, using a bulky amino amide as a transient chiral auxiliary. Various axially chiral styrenes were produced with good yields and high enantioselectivity (up to 95 % yield and 99 % ee). Carboxylic acid derivatives of the resulting axially chiral styrenes showed superior enantiocontrol over the biaryl counterparts in Co^III‐catalyzed enantioselective C(sp³)?H amidation of thioamide. Mechanistic studies suggest that C?H cleavage is the enantioselectivity‐determining step.     

Synthesis of Chiral Aldehyde Catalysts by Pd‐Catalyzed Atroposelective C−H Naphthylation

Chiral aldehyde catalysis opens new avenues for the activation of simple amines. However, the lack of easy access to structurally diverse chiral aldehyde catalysts has hampered the development of this cutting‐edge field. Herein, we report a Pd‐catalyzed atroposelective C?H naphthylation with 7‐oxabenzonorbornadienes for the preparation of axially chiral biaryls with excellent enantioselectivities (up to >99 % ee). This reaction is scalable and robust, which serves as a key step to provide a rapid access to axially chiral aldehyde catalysts through a three‐step C?H functionalization sequence. These chiral aldehydes exhibit better activities and enantioselectivities than the previously reported organocatalysts in the asymmetric activation of glycine derived amides and dipeptides. Moreover, preliminary investigation also discloses that the aldehyde catalyst can effectively override the intrinsic facial selectivity of chiral dipeptide substrates, showcasing the strong chiral induction ability of this type of novel aldehyde catalysts.     

Organocatalytic cycloaddition–elimination cascade for atroposelective construction of heterobiaryls

The first chiral phosphoric acid (CPA) catalyzed cycloaddition–elimination cascade reaction of 2-naphthol- and phenol-derived enecarbamates with azonaphthalenes has been established, providing a highly atroposelective route to an array of axially chiral aryl-C3-benzoindoles in excellent yields with excellent enantioselectivities. The success of this strategy derives from the stepwise process involving CPA-catalyzed asymmetric formal [3 + 2] cycloaddition and subsequent central-to-axial chirality conversion by elimination of a carbamate. In addition, the practicality of this reaction had been verified by varieties of transformations towards functionalized atropisomers.

An organocatalytic asymmetric cycloaddition–elimination cascade reaction of aryl enecarbamates with azonaphthalenes has been developed to access axially chiral heterobiaryls in excellent yields and enantioselectivities.     

The ‘lactone method’: enantioselective preparation of novel P,N-biaryl ligands and their use in the synthesis of the biarylic alkaloids, ancistrotanzanine B and ancistroealaine A

The ‘lactone method’ is a versatile tool for the atroposelective synthesis of axially chiral biaryls. The potential and scope of the concept are highlighted, in particular with respect to its use in the preparation of natural products and chiral auxiliaries. As a new application, the synthesis of novel axially chiral phosphineamines in enantiopure form is described; these ligands were used in the asymmetric Suzuki cross coupling of the molecular portions of the biarylic natural products ancistrotanzanine B and ancistroealaine A.